The present invention relates to a process for the preparation of diesters of poly(oxyalkylene glycols) with amino acid hydrochlorides. More particularly, the present invention relates to a process for the preparation of diesters of poly (oxyalkylene glycols) and amino acid hydrochlorides having structures according to formula I below, 
wherein
R1 and R2 are H, m is an integer from 0 to 12, or
when R1 is H, R2 is xe2x80x94CH2xe2x80x94Phxe2x80x94OH or xe2x80x94CH2xe2x80x94SH or xe2x80x94CH3xe2x80x94(CH)xe2x80x94CH2xe2x80x94CH3 and m is an integer equal to 1,
R is hydrogen or methyl or a mixture of hydrogen and methyl on the individual molecule, and n is an integer of from 0 to 100.
Diesters or diamide derivatives of poly (ethylene glycols) with various amino acids are important monomers that are used in the syntheses of biodegradable polymers. E.g. Pechar et al (1997) reported synthesis of L-glutamic acid based polymeric pro-drugs wherein monomethoxy poly (oxyethylene) monocarboxylic acid was first condensed with para nitro phenol in the presence of dicyclohexylcarboxiimide (DCC) in order to activate the PEG moeity. Subsequently various oligopeptides containing L-glutamic acid were reacted with para-nitrophenyl ester of monomethoxy poly (oxyethylene) carboxylic acid. (M. Pechar, J. Strohalm and K. Ulbrich, Macromol. Chem., 198, 1009 (1997). Kohn et al (1992) reported the synthesis of water soluble poly (ether-urethane) based on PEG and L-lysine. In this, poly (ethylene glycol) was first reacted with phosgene (COCl2) and then treated with N-hydroxysuccinimide in the presence of DCC to obtain activated bis (succinimidyl carbonate) derivative of PEG. This was reacted with lysine methyl ester to obtain poly (ether-urethane) (A. Nathan, D. Bolikal, N. Vyavahare, S. Zalipsky and J. Kohn, Macromolecules 25, 4476 (1992)).
Such indirect routes for linking amino acids with PEG chains were undertaken mainly due to the following reasons. Esters of amino acids are generally synthesised and stored as hydrochloride salts because esters of amino acids with free xe2x80x94NH2 group are prone to undergo diketopiperazine formation. Conventional procedure for synthesis of amino acid ester hydrochloride that comprises reacting alcohol, aminoacid and thionyl chloride is not feasible for poly (ethylene glycol) because of of its bulky chain length. Thus amino acid ester hydrochloride of poly (ethylene glycol) needs to be synthesised in two steps. In the first para toluene sulfonate salt of the diester is synthesised by conventional Dean-Stark type esterification using stoichiometric amounts of amino acid, poly (ethylene glycol) and para toluene sulfonic acid monohydrate. In the second step, paratoluene sulfonate is deblocked by the treatment of base such as triethylamine or sodium bicarbonate. The free ester so synthesised is then converted into the hydrochloride salt by passing dry hydrochloride gas into solution of the ester diethyl ether.
Carbodiimides are strong condensing reagents that are routinely used in condensation reactions of N-protected amino acids. Various speciality protecting groups such as N-carbobenzoxy, N-tertiarybutyloxycarbonyl, etc. are used for this purpose. [M. Bodanzsky and A. Bodanzsky, The Practice of peptide synthesis, Springerverlag, New York, USA, (1984)]. However, the use of the hydrochloride salt as amino protecting group in carbodiimide mediated condensation reactions of amino acids has not been reported as yet.
The only reference relating to the use of amino acid hydrochloride salts as the xe2x80x94NH2 protecting group in carbodiimide mediated condensation reactions was in B. S. Lele, M. A. Gore, M. G. Kulkarni, Synth. Commun. (IN Press, 1999).
Accordingly it is an object of the invention to provide a single step process for the preparation of diesters of poly (oxyalkylene glycol) and amino acids.
It is a further object of the invention to provide a process for the preparation of diesters of poly (oxyalkylene glycols) and amino acids that can be carried out under mild conditions and is generally applicable to several amino acids.
It is another object of the invention to provide a process for the preparation of diesters of poly (oxyalkylene glycols) and amino acids that allows easy esterification.
Accordingly the present invention relates to a process for the preparation of diesters of poly (ethylene glycol) of formula I below 
wherein
R1 and R2 are H, m is an integer from 0 to 12, or
when R1 is H, R2 is xe2x80x94CH2xe2x80x94Phxe2x80x94OH or xe2x80x94CH2xe2x80x94SH or xe2x80x94CH3xe2x80x94(CH)xe2x80x94CH2xe2x80x94CH3 and mn is an integer equal to 1,
R is hydrogen or methyl or a mixture of hydrogen and methyl on the individual molecule, and n is an integer of from 0 to 100, said process comprising reacting poly (oxyalkylene glycol) and amino acid hydrochloride in the presence of a condensing agent in a suitable solvent at a temperature in the range of 0xc2x0 C. to room temperature for a period ranging between 1 hour to 24 hours, filtering the reaction mixture, pouring the filtrate into another solvent, which is a nonsolvent for the products and isolating the precipitated products.
In one embodiment of the invention, poly(oxyalkylene glycol) may be selected from compounds of the formula HOCH2xe2x80x94CHRxe2x80x94(CH2xe2x80x94CHRxe2x80x94Oxe2x80x94)nxe2x80x94CH2xe2x80x94CHRxe2x80x94OH wherein R is hydrogen, methyl or a mixture of hydrogen and methyl on the individual molecule, n is an interger which represents the average number of oxyalklene groups, and is preferably from 0 to 100.
In yet another embodiment of the invention, the amino acid may be selected from trifunctional and difunctional amino acids and their respective hydrochlorides.
In a further embodiment of the invention, the trifunctional amino acids are selected from tyrosine and cysteine.
In a further embodiment of the invention, the difunctional amino acids are selected from glycine, isoleucine, 6 amino caproic acid, 11 amino caproic acid.
In yet another embodiment of the invention, the condensing agent may be selected from carbodiimides such as dicyclohexyl carbodiimide, diisopropyl carbodiimide or the like.
In another embodiment of the invention, the suitable solvent may be selected from acetonitrile, tetrahydrofuran, dioxane, dimethyl formamide and the like.
The process is typically carried out under mild conditions. Stoichiometric amounts of poly (oxyalkylene glycol) and amino acid hydrochloride are dissolved in a suitable solvent and the stoichiometric amount of a carbodiimide is added and the reaction mixture is stirred at room temperature for 12 hours. After this, the reaction mixture is filtered to remove the urea salts formed due to the condensation reaction. The clear solution containing the diester of poly (oxyalkylene glycol) and amino acid hydrochloride is then poured into another solvent which is a non solvent for the diester. Precipitated diester is then isolated.